PROJECT SUMMARY/ABSTRACT Rheumatoid arthritis (RA) is the most common adult form of inflammatory polyarthritis and is associated with substantial disability and increased mortality. Current biologic therapies are effective in a subset of patients, but there is a clear need for improved therapeutic approaches. Deletion of the SLC2A3 gene (encoding the GLUT3 glucose transporter protein) on chromosome 12 is strongly protective for RA in humans. In order to harness the protective effect of this genetic variant for use in developing preventative or therapeutic measures for RA, it is crucial to understand the cell types, cell functions and disease pathogenic mechanisms altered by SLC2A3 haploinsufficiency. The reduced risk for RA in deletion-carriers suggests that corresponding reduced expression of GLUT3 in cells dependent on GLUT3 for their function reduces risk for RA development; we have shown reduced expression in both T cells and myeloid cell types of deletion-carriers. As CD4 T cells are considered to be a key driver in the initiation of RA, and recent literature indicate that GLUT3 is required for normal T cell proliferation, our primary hypothesis is that the arthritis protective mechanism is T cell dependent. The specific aims are to: 1) elucidate the role of Glut3 haploinsufficiency on the development of mouse models of RA, 2) study the requirement for Glut3 sufficiency in CD4+ T cell functions in Slc2a3 conditional knockout mice 3) identify the cell-type intrinsic mechanism of the protective effect of Slc2a3 hemizygosity, and 4) determine requirement of GLUT3 sufficiency for human CD4+ T cell functions and RA-like phenotypes. The above abstract constitutes the revised research proposal component of a K01 career development award application of Dr. Kim Simpfendorfer. Together with the career development plan, this proposal is designed to allow Dr. Simpfendorfer the support and foundation to investigate the validity of GLUT3 as a therapeutic target in RA. Specifically, Dr. Simpfendorfer will receive training and mentorship in research management, leadership and animal models of RA as well as further training in autoimmune disease pathogenesis in mouse and human systems. The achievement of these goals will be accomplished through the mentorship from Dr. Peter K Gregersen, and input from the advisory committee of Drs. Betty Diamond, Laurence Morel, Sun Jung Kim and Yong Rui Zou. Additionally, Kim will receive technical training in animal models of arthritis from Drs. Max Brenner, Anne Davidson and Myoungsun Son. The Feinstein Institute for Medical Research is an ideal institutional environment for Dr. Simpfendorfer's research and career development due to training and mentoring resources, unique human resources such as the Genotype and Phenotype Registry, and the cross- disciplinary expertise of the proposed mentor, advisory committee and institutional faculty. Furthermore, the Feinstein Institute is adequately equipped with the required facilities and equipment to enable productive progress of the described research proposal.